EP0207375B1 - Stéroido[3,2-c]-pyrazoles utiles comme anti-androgènes et leur préparation - Google Patents

Stéroido[3,2-c]-pyrazoles utiles comme anti-androgènes et leur préparation Download PDF

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Publication number
EP0207375B1
EP0207375B1 EP86108328A EP86108328A EP0207375B1 EP 0207375 B1 EP0207375 B1 EP 0207375B1 EP 86108328 A EP86108328 A EP 86108328A EP 86108328 A EP86108328 A EP 86108328A EP 0207375 B1 EP0207375 B1 EP 0207375B1
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Prior art keywords
compound
formula
mole
pyrazol
methylsulfonyl
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EP86108328A
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German (de)
English (en)
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EP0207375A1 (fr
Inventor
Robert George Christiansen
Malcolm Rice Bell
John Lawrence Herrmann, Jr.
Chester Joseph Opalka, Jr.
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STWB Inc
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Sterling Drug Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only
    • C07J71/0047—Nitrogen only at position 2(3)

Definitions

  • the invention relates to steroido[3,2-c]pyrazoles, which are useful as antiandrogenic agents, and processes for preparation, method of use and compositions thereof.
  • U.S. Pat. 3 704 295 describes steroido[3,2-c]pyrazoles having a substituent designated R' on one or the other of the pyrazole nitrogen atoms wherein R' includes lower-alkyl radicals, e.g. methyl, ethyl, propyl, isopropyl, butyl, and the like; monocarbocyclic aryl radicals, e.g. phenyl, p-tolyl, and the like; lower-alkanoyl radicals, e.g. acetyl, propionyl, butyryl, and the like; monocarbocyclic aroyl radicals, e.g.
  • monocarbocyclic aryl-lower-alkanoyl radicals e.g. phenylacetyl, ⁇ -phenylpropionyl, p-chlorophenylacetyl, and the like
  • monocarbocyclic aryloxy-lower-alkanoyl radicals
  • the starting mono-substituted hydrazines are mono-acyl hydrazines, semicarbazide or aminoguanidine, respectively.
  • the compounds wherein R' represents hydrogen can be utilized as intermediates for preparing the compounds wherein R' represents an acyl radical or the carbamyl radical by reacting said compounds wherein R' represents hydrogen with the appropriate acid anhydride, or with cyanic acid (an alkali metal cyanate in the presence of mineral acid), respectively.
  • the steroido[3,2-c]pyrazoles of the above patent are described as possessing useful metabolic, hormonal or anti-hormonal properties. In particular they exhibit one or more of the following activities: anabolic, androgenic, pituitary inhibiting, estrogenic, progestational and adrenal cortical.
  • the present invention relates to a compound having the structural formula wherein
  • One process of preparing a compound of Formula I comprises sulfonylating the corresponding compound having the structural formula with the corresponding compound having the structural formula wherein Q is Cl, Br or OSO 2 X.
  • a second process comprises condensing the corresponding compound having the structural formula with the corresponding compound having the structural formula wherein R' is CH 3 or CH 3 CH 2 .
  • a third process comprises condensing the corresponding compound having the structural formula with the corresponding compound having the structural formula wherein R' is CH 3 , CH 3 CH 2 or C 6 H 5 .
  • a pharmaceutical composition comprises an antiandrogenically effective concentration of a compound of Formula I and a pharmaceutically acceptable vehicle.
  • the compounds of Formula II are steroido[3,2-c]pyrazoles and are described by, or can be made by the methods described in, above-cited U.S. Pat. 3 704 295.
  • the compounds of Formula III wherein Q is Cl, which are sulfonyl chlorides, are commercially available.
  • the compounds of Formula III wherein Q is OS0 2 X are sulfonic acid anhydrides and are commercially available or can be made from the corresponding sulfonic acids by warming with phosphorous pentoxide.
  • the compounds of Formula III wherein Q is Br, which are sulfonyl bromides, can be made from the corresponding sulfonic anhydrides by heating with hydrogen bromide at 105°C.
  • the compounds of Formula IV which are 2a-dimethoxymethyl or diethoxymethyl-3-keto steroids, are made by dimethoxymethylating or diethoxymethylating the corresponding 3-keto steroids with the reagent made from trimethyl orthoformate or triethyl orthoformate (the latter is preferred) and boron trifluoride etherate (dimethoxycarbenium or diethoxycarbenium fluoborate) at low temperature by the method of Mock et al (William L. Mock and Huei-Ru Tsou, J. Org. Chem., 1981, vol. 46, pp. 2557 - 2561).
  • the compounds of Formula V which are sulfonyl hydrazides, are commercially available or can be made from the corresponding sulfonyl chlorides and hydrazine hydrate in ethanol.
  • the compounds of Formula VI are 2-acetoxymethylene, propionoxymethylene or benzoyloxymethylene-3- keto steroids and are made from the corresponding known 2-hydroxymethytene-3-keto steroids and acetic anhydride or propionic anhydride or a mixed anhydride thereof, for example, the mixed anhydride made from the acid and methanesulfonyl chloride, or benzoyl chloride, respectively.
  • the first process is carried out at a temperature in the range of 0 - 100°C. in an inert solvent and in the presence of an acid acceptor for the hydrogen chloride, hydrogen bromide or sulfonic acid produced as a byproduct of the reaction.
  • the acid acceptor is preferably a tertiary amine.
  • the inert solvent and the acid acceptor can be the same substance, for example, pyridine, which is the preferred inert solvent and acid acceptor. Sulfonylation occurs predominantly at the 1'-position of the pyrazole ring but can also occur to the extent of up to about 30 % at the 2'-position of the pyrazole ring.
  • Separation of the desired 1'-isomer from the 2'-isomer may therefore be necessary, for example, by fractional crystallization, column chromatography or high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the second process which produces the 1'-isomer of Formula I selectively, is carried out at a temperature in the range of 0 - 100° C. in an inert solvent.
  • Tetrahydrofuran is the preferred inert solvent.
  • the third process which also produces the 1'-isomer of Formula I selectively, is carried out at a temperature in the range of 0 - 100°C. in an inert solvent.
  • Acetic acid or a mixture of acetic acid and dichloromethane is the preferred solvent.
  • a compound of Formula I wherein Y-Z is can be made from the corresponding compound of Formula I wherein Y-Z is respectively, by epoxidation with a peracid, for example, m-chloroperbenzoic acid.
  • a compound of Formula I wherein R 17 ⁇ is H and R 17 ⁇ is OH can be made from the corresponding 17-keto (17a and 17P together are oxo) compound (obtained by conversion by hydrolysis of the compound of Formula I where R 17 ⁇ and R 1711 together are OCH 2 CH 2 O) by reduction with a metal hydride, for example, sodium borohydride.
  • a compound of Formula I wherein R 17 ⁇ is H and R 17P is OCOCHCI 2 can be made from the corresponding compound of Formula I wherein R 17 ⁇ is H and R 17P is OH by dichloroacetylation using, for example, dichloroacetic anhydride.
  • a compound of Formula I wherein R 17 ⁇ is OCH 2 SOCH 3 or OCH 2 SO 2 CH 3 can be made from the corresponding compound of Formula I wherein R 17P is OCH 2 SCH 3 by S-oxidation using a peracid, for example, m-chloroperbenzoic acid.
  • structures of products are inferred from structures of starting materials and expected courses of preparative reactions. Structural confirmation and estimation of purity of starting materials and products are measured by melting temperature range (m.r.), elemental analysis, infrared (IR) spectral analysis, ultraviolet (UV) spectral analysis, nuclear magnetic resonance (NMR) spectral analysis, gas chromatography (GC), high pressure liquid chromatography (HPLC) and thin layer chromatography (TLC).
  • melting temperature range m.r.
  • elemental analysis infrared (IR) spectral analysis
  • UV ultraviolet
  • NMR nuclear magnetic resonance
  • GC gas chromatography
  • HPLC high pressure liquid chromatography
  • TLC thin layer chromatography
  • the crystalline product (44.07 g) was purified by HPLC on silica gel using dichloromethane-ether (9 : 1) as eluant followed by recrystallization from methanol, affording (5 ⁇ ,17 ⁇ )-17-methyl-1'-(methylsulfonyl)-1'H-androstano[3,2-c]-pyrazol-17-ol (25.47 g, 55 % yield, m.r. 189 - 190°C), the compound of Formula I wherein X, R 10 and R 17 ⁇ are methyl, Y-Z is
  • the crystalline product (16.75 g) was purified by HPLC on silica gel using dichloromethane-ether (9 : 1) as eluant followed by recrystallization from methanol, affording (5 ⁇ ,17 ⁇ )-1'-(ethylsulfonyl)-1'H-pregn-20-yno(3,2-c]pyrazol-17-ol (12.11 g, 58 % yield, m.r. 191 - 193 ⁇ C), the compound of Formula I wherein X is CH 3 CH 2 , Y-Z is
  • the crystalline product (23.54 g) was purified by HPLC on silica gel using dichloromethane-ether (19 : 1 ) as eluant followed by recrystallization from methanol, affording (5 ⁇ ,17 ⁇ )-1'-(propylsulfonyl)-1'H-pregn-20-yno[3,2-c]pyrazol-17-ol (10.97 g, 52 % yield, m.r. 182 - 183° C), the compound of Formula I wherein X is CH 3 CH 2 CH 2 , Y-Z is
  • the eluant of fractions 1 - 2 was dichloromethane-hexane (3 : 1), of fractions 3 - 7 dichloromethane-hexane (7 : 1), of fractions 8 - 18 dichloromethane, of fractions 19 - 22 dichloromethane- ether (19 : 1).
  • chloromethylsulfonyl chloride (1.7 ml, 0.019 mole; 4 ml, 0.044 mole) was added to a solution of (5 ⁇ ,17 ⁇ )-1'H-pregn-20-yno[3,2-c]pyrazol-17-ol (3.38 g, 0.0100 mole; 8.5 g, 0.025 mole) in pyridine (20 ml, 35 ml).
  • pyridine 20 ml, 35 ml.
  • the resulting solution was allowed to stand at room temperature for 1 - 3 hr, then poured into water (300 ml, 350 ml).
  • the gumming products were purified by a combination of crystallization from cyclohexane or tetrachloromethane and column chromatography on silica gel using dichloromethane as eluant and combined, affording (5 ⁇ ,17 ⁇ )-1'-[(chloromethyl)sulfonyl]-1'H-pregn-20-yno[3,2-c]pyrazol-17-ol (5.4 g, 34 % yield, m.r. 168 - 170°C), the ccmpound of Formula I wherein X is CICH 2 , Y-Z is is H, R 10 is CH 3 , R 17 ⁇ . is C ⁇ CH and R 17 ⁇ is OH.
  • the aqueous layer was extracted with dichloromethane (250 ml).
  • the combined dichloromethane layers were washed twice with cold hydrochloric acid (2N, 1200 ml, 600 ml), then with half-saturated aqueous sodium bicarbonate solution (800 ml), dried and stripped of dichloromethane.
  • the residue was triturated with hexane, affording (2 ⁇ ,5 ⁇ ,17 ⁇ )-2-(diethoxymethyl)-17-[(tetrahydro-2H-pyran-2-yl)oxy]an- drostan-3-one (70.57 g, 49 % yield, m.r. 165 - 168° C).
  • Dichloroacetic anhydride (4.60 g, 0.02 mole) was added with cooling to a solution of (17 ⁇ )-4-methyl-1'-(methylsulfonyl)-l'H-androst-4-eno[3,2-c]pyrazol-17-ol (product of Example 13, 4.05 g, 0.0100 mole) in pyridine (25 ml).
  • the mixture was diluted with hydrochloric acid (2N, 200 ml) and extracted with dichloromethane (100 ml).
  • the dichloromethane extract was washed with saturated aqueous sodium hydroxide solution (100 ml), dried and stripped of volatiles.
  • Example 21 By the method of Example 21 (5 ⁇ ,17 ⁇ )-1'-(methylsulfonyl)-1'H-androstano[3,2-c)pyrazol-17-ol (product of Example 12, 11.78 g, 0.0300 mole) was dichloroacetylated using dichloroacetic anhydride (14.39 g, 0.0600 mole plus 1 ml) in pyridine. The reaction mixture was quenched in hydrochloric acid (2N, 1 I). Recrystallization of the crude product (15.52 g, m.r.
  • m-Chloroperbenzoic acid (assumed to be 80 % pure, 11.86 g, 0.055 mole) was added with stirring to a solution of (5 ⁇ ,17 ⁇ )-1'-(methylsulfonyl)-17-[(methylthio)methoxy]pregn-20-yno[3,2-c]pyrazole (11.92 g, 0.0250 mole) in dichloromethane (200 ml) maintained at 0°C.
  • m-Chloroperbenzoic acid (assumed to be 80 % pure, 5.39 g, 0.025 mole) was added with stirring and ice bath cooling to a solution of (5a,17a)-1 -(methylsulfonyl)-17-[(methylthio)methoxy]pregn-20-yno[3,2-c]pyrazole (11.9 g, 0.025 mole) in dichloromethane (200 ml). Stirring was continued and unreacted starting material was shown by TLC to be present after one day. More m-chloroperbenzoic acid (0.50 g) was added and stirring was continued for 1 hr.
  • prostate glands from 24-hr castrated adult male rats weighing approximately 250 g were homogenized in aqueous pH 7.4 buffer containing triaziquone (10 mM), sodium molybdate (20 mM), 1,4-dithiothreitol (2.0 mM) and glycerol (10 %). The homogenate was centrifuged at the equivalent of 105,000 g for 1 hr. Aliquots of the supernatant liquid (cytosol) were incubated with methyltrienolone labelled with tritium in the 17a-methy!
  • Triamcinolone acetonide (1 ⁇ M) was added to the cytosol before incubation to block the low affinity binding of labelled methyltrienolone to progesterone and glucocorticoid receptors. After the 1 hr or 18 hr incubation period an aqueous suspension of dextran (T-70, 0.05 %) - coated charcoal (1 %) was added to the incubation mixture and incubation was continued for 5 min.
  • the incubation mixture was centrifuged to remove charcoal (nonprotein)-bound labelled methyltrienolone. The supernatant was separated and its radioactivity was counted to determine the concentration of protein-bound labelled methyltrienolone. The relative binding affinity was calculated as the concentration of test compound required to reduce the concentration of protein-bound labelled methyltrienolone by 50 % as a percentage relative to unlabelled methyltrienolone. Androgens including the naturally occurring testosterone and 5a-dihydrotestosterone (stanolone) and the synthetic methyltrienolone and stanozolol (a steroido[3,2-c]pyrazole of above-cited U.S. Pat.
  • the antiandrogenically effective amount of the compound of Formula I can be estimated from the foregoing test results.
  • Most preferably the compound of Example 1 or the compound of Example 16 is used.
  • the compounds are used in the human male in the treatment of benign prostatic hypertrophy or in the human female in the treatment of polycystic ovarian disease or in other human disease or metabolic disorder amenable to treatment with an antiandrogenic agent.
  • the compound of Formula I can be used alone but preferably is incorporated in a pharmaceutical composition.
  • the pharmaceutical compositions can be prepared for oral, parenteral, rectal or vaginal administration and can be in solid or liquid dosage form including capsules, tablets, suppositories, solutions, suspensions and emulsions. Conventional pharmaceutically acceptable vehicles and techniques are used in preparing these dosage forms.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Claims (10)

1. Composé ayant la formule développée
Figure imgb0077
dans laquelle
X est CH,, CH3CH2 CH3CH2CH2 ou ClCH2;
Y-Z est
Figure imgb0078
Figure imgb0079
R6 est H ou CH3 quand Y-Z est CH = C ou H quand Y-Z est autre que CH = C;
R10 est H ou CH3;
R17α pris seul est H, CH3, CH2CH3, CH=CH2, C=CH ou C≡ Br;
R17β pris seul est OH, OCOCHCl2, OCOCF3, OCH3, OCH2SCH3, OCH2SOCH3, OCH2SO2CH3 ou OCH(CH2)40, et R17α pris avec R17β est OCH2CH2O.
2. Composé selon la revendication 1, dans lequel X est CH3, Y-Z est
Figure imgb0080
R17α est CH3 ou C≡ CH et R17β est OH.
3. (5α,17α)-1'-(méthylsulfonyl)-1'H-prègn-20-yno[3,2-c] pyrazole-17-ol selon la revendication 2.
4. (5α,17β)-17-méthyl-1'-(méthysulfonyl)-1'H-androstano-[3,2-c]-pyrazole-17-ol selon la revendication 2
5. (17β)-4,17-diméthyl-1'-(méthylsulfonyl)-1'H-androst-4-éno[3,2-c]-pyrazole-17-ol selon la revendication 2.
6. (17α)-4-méthyl-1'-(méthylsulfonyl)-1'H-prègn-4-èn-20-yno(3,2-c]-pyrazole-17-ol selon la revendication 2
7. 4-méthyl-1'-(méthylsulfonyl)-1'H-androst-4-èno-[3,2-c] pyrazole-17-one.
8. Procédé de préparation d'un composé selon la revendication 1 ou 2, qui comprend:
a) la sulfonylation du composé correspondant ayant la formule développée:
Figure imgb0081
dans laquelle
Y-Z, R6, R10, R17α et R17β sont tels qu'ils ont été définis dans la revendication 1, avec le composé correspondant ayant la formule développée III XSO2Q, dans laquelle Q est CI, Br ou OS02X,
b) la condensation du composé correspondant ayant la formule développée:
Figure imgb0082
dans laquelle
Y-Z, R6, R10, R17α et R17β sont tels qu'ils ont été définis dans la revendication 1, avec le composé correspondant ayant la formule développée V XSO2NHNH2, R étant CH3 ou CH3CH2, ou
c) la condensation du composé correspondant ayant la formule développée:
Figure imgb0083
dans laquelle
Y-Z, Rs, R10, R17α et R17β sont tels qu'ils ont été définis dans la revendication 1, avec le composé correspondant ayant la formule développée V XSO2NHNH2, R' étant CH3, CH3CH2 ou C6H5,;
si on le désire, l'hydrogénation catalytique d'un composé de formule I obtenu dans lequel R17α est CH=CH pour obtenir le composé correspondant dans lequel R17α est C=CH2,
si on le désire, l'hydrogénation catalytique d'un composé de formule 1 obtenu dans lequel R17α est CH=CH2 ou C≡CH pour obtenir le composé correspondant dans lequel R17α est CH2CH3,
si on le désire, la bromation d'un composé de formule 1 obtenu dans lequel R17α est C≡CH pour obtenir le composé correspondant dans lequel R17α, est C≡CBr,
si on le désire, l'époxydation avec un peracide d'un composé de formule I obtenu dans lequel Y-Z est CH = C ou CCH3 = C pour obtenir le composé correspondant dans lequel Y-Z est
Figure imgb0084
respectivement.
si on le désire, la conversion d'un composé de formule 1 obtenu dans lequel R17α et R17β forment ensemble OCH2CH2O en un composé intermédiaire selon la formule I dans lequel en outre R17α + R17β forment ensemble un groupe céto et la réduction de ce dernier composé par un hydrure de métal pour préparer le composé dans lequel R17α est H et R17β est OH,
si on le désire, la dichloroacétylation d'un composé de formule I obtenu dans lequel R17α est H et R17β est OH, pour obtenir le composé correspondant dans lequel R17α est H et R17β est OCOCHCI2, et
si on le désire, l'oxydation avec un peracide d'un composé de formule I obtenu dans lequel R17β est OCH2SCH3 pour obtenir le composé correspondant dans lequel R17β est OCH2SOCH3 ou OCH2SO2CH3.
9. Composition pharmaceutique comprenant une concentration efficace du point de vue antiandrogénique d'un composé selon l'une quelconque des revendications 1 à 6 et un excipient pharmaceutiquement acceptable.
10. Utilisation d'un composé selon l'une quelconque des revendications 1 à 6 pour préparer un médicament destiné à provoquer une réponse antiandrogénique chez un mammifère.
EP86108328A 1985-06-24 1986-06-19 Stéroido[3,2-c]-pyrazoles utiles comme anti-androgènes et leur préparation Expired EP0207375B1 (fr)

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MYPI87002259A MY101921A (en) 1985-06-24 1987-09-29 Steroido (3, 2-c) pyrazoles useful as antiandrogenic agents and preparation thereof

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US74837885A 1985-06-24 1985-06-24
US748378 1985-06-24
US849582 1986-04-08
US06/849,582 US4684636A (en) 1985-06-24 1986-04-08 Antiandrogenic sulfonylsteroidopyrazoles and processes for preparation method of use and compositions thereof

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EP0207375B1 true EP0207375B1 (fr) 1989-08-02

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EP (1) EP0207375B1 (fr)
KR (1) KR910002228B1 (fr)
AR (2) AR242798A1 (fr)
AT (1) ATE45164T1 (fr)
AU (1) AU581767B2 (fr)
CA (1) CA1255294A (fr)
DE (1) DE3664775D1 (fr)
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ES (2) ES8800690A1 (fr)
FI (1) FI83425C (fr)
GR (1) GR861613B (fr)
IL (1) IL79046A0 (fr)
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NO (1) NO166039C (fr)
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US5134135A (en) * 1990-06-21 1992-07-28 Sterling Drug Inc. Antiandrogenic sulfonylsteroidooxazoles
US5053405A (en) * 1990-06-21 1991-10-01 Sterling Drug Inc. Antiandrogenic sulfonylsteroidothiazoles
US5100882A (en) * 1990-06-21 1992-03-31 Sterling Drug Inc. Antiandrogenic sulfonylsteroidofurans
DE4021433A1 (de) * 1990-07-04 1992-01-09 Schering Ag Antiandrogene mit steroid(3,2-c)pyrazol-struktur
US5223268A (en) * 1991-05-16 1993-06-29 Sterling Drug, Inc. Low solubility drug-coated bead compositions
US5175155A (en) * 1991-10-07 1992-12-29 Sterling Winthrop Inc. Win 49596-finasteride method of use and compositions
DE4227465A1 (de) * 1992-08-17 1994-02-24 Schering Ag Antiandrogene Steroide mit aneliertem Fünfring
AU2002222567B2 (en) * 2000-12-01 2007-05-10 Kyowa Hakko Kirin Co., Ltd. Composition improved in solubility or oral absorbability

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NL237293A (fr) * 1959-02-16
US2945852A (en) * 1959-05-20 1960-07-19 Searle & Co 17-oxygenated 9alpha-substituted androstano [3, 2-c] pyrazoles and derivatives
US4356175A (en) * 1978-10-10 1982-10-26 The Upjohn Company 17β-Hydroxy-17α-methyl-5α-androstano-[3,2-c]pyrazole 17-methyl ether
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ZA864199B (en) 1987-01-28
CA1255294A (fr) 1989-06-06
ES557699A0 (es) 1988-03-01
FI862637A0 (fi) 1986-06-19
NO862506L (no) 1986-12-29
PH22087A (en) 1988-05-20
ES8800690A1 (es) 1987-11-16
DK293786A (da) 1986-12-25
EP0207375A1 (fr) 1987-01-07
ATE45164T1 (de) 1989-08-15
US4684636A (en) 1987-08-04
MY101921A (en) 1992-02-15
ES8801929A1 (es) 1988-03-01
AR242798A1 (es) 1993-05-31
PT82837A (en) 1986-07-01
KR870010074A (ko) 1987-11-30
FI83425C (fi) 1991-07-10
FI83425B (fi) 1991-03-28
NO166039B (no) 1991-02-11
NZ216438A (en) 1989-01-06
IL79046A0 (en) 1986-09-30
NO862506D0 (no) 1986-06-23
PT82837B (pt) 1988-04-21
AU5896586A (en) 1987-01-08
KR910002228B1 (ko) 1991-04-08
DK293786D0 (da) 1986-06-23
AU581767B2 (en) 1989-03-02
DE3664775D1 (en) 1989-09-07
ES556422A0 (es) 1987-11-16
NO166039C (no) 1991-05-29
FI862637A (fi) 1986-12-25
GR861613B (en) 1986-10-30
AR243201A1 (es) 1993-07-30

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